Abstract
Individuals with Alzheimer's disease (AD) are in susceptible patient groups in which pain is an important clinical issue that is often underdiagnosed. However, it is unclear whether decreased pain complaints in patients with AD result from elevated pain tolerance or an impaired ability to communicate sensations. Here, we explored if AD-related pathology is present in key regions of the pain pathway and assessed whether nociceptive thresholds to acute noxious stimulation are altered in the double-mutant APPswe × PS1.M146V (TASTPM) transgenic mouse model of AD. TASTPM mice exhibited an age-dependant cognitive deficit at the age of 6 months, but not at 4 months, a deficit that was accompanied by amyloid plaques in the cortex, hippocampus, and thalamus. In the spinal cord, β-amyloid (APP/Aβ) immunoreactivity was observed in dorsal and ventral horn neurons, and the expression of vesicular glutamate transporter 2 (VGLUT2) was significantly reduced, while the expression of the inhibitory peptides enkephalins was increased in TASTPM dorsal horn, consistent with an increased inhibitory tone. TASTPM mice displayed reduced sensitivity to acute noxious heat, which was reversed by naloxone, an opioid antagonist. This study suggests that increased inhibition and decreased excitation in the spinal cord may be responsible for the reduced thermal sensitivity associated with AD-related pathology.
Highlights
Alzheimer’s disease (AD) is a progressive and irreversible agerelated neurodegenerative disease
Amyloid deposits were detected in 12-month-old TASTPM mice and these deposits were accompanied by barriers formed by astrocytes (GFAP, Fig. 2A–C) and microglia (IBA1, Fig. 2D–F)
We observed a significant increase of enkephalin immunoreactivity in laminae I and II of the dorsal horn of 6-month-old TASTPM mice compared with WT mice (Fig. 7A–C)
Summary
Alzheimer’s disease (AD) is a progressive and irreversible agerelated neurodegenerative disease. It is the most common form of dementia (.60%) in the elderly population, affecting around 35 million people worldwide and ;800,000 people in the United Kingdom.[25,31,43] The prevalence of AD is approximately 5% in people older than 65 years, increasing to approximately 30% by the age of 85 years.[22] The aetiology of the disease is complex due to the heterogeneity of the disorder. Alzheimer’s disease is clinically characterised by a global deficit in cognition ranging from loss of memory to impaired judgement and reasoning.[43] Neuropathological hallmarks of AD are extracellular b-amyloid (Ab) plaques and intracellular neurofibrillary tangles composed of abnormally hyperphosphorylated microtubule-associated protein tau. These hallmarks are accompanied by neuronal loss, synaptic dysfunction, brain atrophy, and inflammation.[40]
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